Optogenetics is one of the most important technological breakthroughs in neuroscience during the past decade, and holds tremendous promise for dissecting the mechanisms of neurologic disease and for treating a range of disorders. Optogenetic devices are ion channels or pumps that can be regulated by light, thus permitting the investigator to turn neuronal activity on and off with high spatial and temporal precision. Optogenetic devices come in two basic varieties: optogenetic activators which cause a cell to depolarize upon exposure to light and optogenetic inhibitors which cause a cell to hyperpolarize. Since optogenetic devices are genetically encoded, their expression can be precisely targeted to defined subpopulations of cells for both experimental and therapeutic purposes.
Optogenetic approaches can be applied to virtually any organ system, but they are particularly useful in electrically active cells. For this reason, most research using optogenetic approaches has focused on the brain, the retina, and the heart. In basic studies, optogenetic tools permit a scientist to exert unprecedented control over the activity of neuronal circuits, thus allowing a deeper understanding of circuit function. In the applied arena, a range of therapeutic applications of optogenetics can be envisioned. First, in combination with recently developed wireless LED devices, optogenetic approaches may soon permit the direct stimulation of subpopulations of brain cells within defined nuclei without the need for invasive, indwelling electrodes. This kind of therapy could eventually revolutionize treatment of diseases such as Parkinson's disease, which in some cases is treated with chronic electrodes placed in the subthalamic nuclei.
Another potential application would be as an ‘all optical’ pacemaker in the heart of patients with cardiac arrhythmias. Currently, such patients require cumbersome indwelling wires to be implanted in the tissues of their heart. With optogenetics, one could target the pacemaker cells themselves with optogenetic devices (via a gene therapy vector such as adeno-associated virus [AAV]) and then implant a minute wireless LED device to control the cells. This approach could greatly simplify the use of pacemakers and improve the lives of the many patients requiring them.
There are over 200 genetically distinct forms of retinal degeneration that cause severe vision loss or complete blindness in millions of people worldwide. Both simple (Mendelian) and complex (non-Mendelian) forms of retinal degeneration exist. The final common pathogenetic mechanism in all of these conditions is the progressive loss of both rod and cone photoreceptors via cell death. Once photoreceptors are lost, blindness ensues. There is no cure for any of these genetic forms of blindness.
In contrast to traditional gene therapy that attempts to replace or repair a defective gene or bypass the genetic defect through correction of the protein deficiency or dysfunction, optogenetic approaches to therapy can be used to endow normally non-photosensitive cells in the retina with the ability to respond to light, thus restoring useful vision to the patient. Unlike retinal chip implants that provide extracellular electrical stimulation to bipolar or ganglion cells, optogenetics-based therapies stimulate the cells from inside the cell.
The most commonly used optogenetic devices operate in the 450-600 nm range, presenting two challenges to the investigator: (1) light in this range is strongly scattered and absorbed by neural tissue and blood, limiting the tissue depth at which optogenetic devices can be effectively utilized; and (2) many optogenetic sensors that report physiological states (e.g., calcium levels or voltage) have activation or emission spectra that strongly overlap the wavelength range of the optogenetic devices, thus complicating their simultaneous use. Thus there is a need for optogenetic devices with red-shifted excitation spectra, because longer wavelength light penetrates more deeply into tissue and red-shifting reduces the spectral overlap with sensors.